Prevention of contact allergy by coadministration of a corticosteroid with a sensitizing drug

ABSTRACT

A method of preventing sensitization in transdermal drug delivery by the inclusion of a corticosteroid, which will be co-extensively coadministered with the sensitizing agent.

This application is a divisional of U.S. Pat. application Ser. No.07/604,840 filed Nov. 27, 1990, now U.S. Pat. No. 5,077,054.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the transdermal delivery of drugs. Moreparticularly, this invention relates to the prevention of contactsensitization. Still more particularly, but without limitation thereto,this invention relates to the co-extensive coadministration ofcorticosteroids and sensitizing drugs.

2. Description of the Prior Art

The transdermal route of parenteral delivery of drugs provides manyadvantages and transdermal systems for delivering a wide variety ofdrugs or other beneficial agents are described in U.S. Pat. Nos.3,598,122, 3,598,123, 4,286,592, 4,314,557, 4,379,454, 4,559,222 and4,573,995, for example, all of which are incorporated herein byreference.

These transdermal drug delivery systems are well known. In many cases,drugs which would appear to be ideal candidates for transdermal deliveryhave a tendency to sensitize the patient, leading to skin reactions, acondition known as contact sensitivity or contact allergy. Therefore,despite the development of the art, there has remained a continuing needfor improved methods of overcoming sensitization problems.

Sensitization is a two-phase process involving totally distinctbiological mechanisms. The first is the induction phase where the skinis initially exposed to the sensitizing drug. During this phase,generally no skin reaction may be noted. In the induction phase, thesensitizing drug or antigen is presented to the T-lymphocytes by theLangerhans cells of the epidermis, either in situ of in the draininglymph node. As a consequence, cells which recognize the antigen,proliferate and to some extent differentiate.

The second subsequent phase, following the establishment of contactallergy, is elicitation where subsequent exposure to the sensitizingdrug results in a manifested skin reaction. This condition is known ascontact dermatitis. During elicitation, the antigen is once againpresented mainly on Langerhans cells. The T-cells which haveproliferated upon prior exposure now come to the treated site andinitiate toxic events which result in local inflammation.

Contact sensitization is a completely different process than irritation.Irritation is caused by and therefore relieved by a different mechanismthan that of sensitization. Irritation depends upon a variety of factorsincluding, but not limited to, change in pH and bacterial overgrowth.Ultimately, irritation is the result of damage to the cells by cellularresponse to a toxic agent, i.e. one that irritates. Sensitization on theother hand, is the result of an allergic cellular response to an agentwhich is not necessarily intrinsically toxic.

Corticosteroids are commonly used to alleviate the after-effects ofelicitation of contact sensitivity and of irritation and areadministered either alone or in combination with a drug, for their knownanti-inflammatory action, and have successfully worked to diminish thesymptoms of: (1) allergic reaction, i.e. after sensitization hasoccurred, J. Foussereau, C. Benezra, H. I. Maibach & N. Hjorth,Occupational Contact Dermatitis, Clinical and Chemical Aspects (W. B.Saunders Company, 1982); and (2) irritation, Japanese Kokai No.60-23,312, Nitto Electric Ind. Co. (1985).

However, in general it is difficult to significantly reduce the responseonce the skin has been sensitized. For that reason, this invention isdirected towards "before-the-fact" effectiveness, i.e. reduction orelimination of the induction phase of sensitization before seriousreactions occur, rather than treating problems after pain and discomforthave occurred.

Corticosteroids are well known to reduce inflammation caused byirritation. For example, in Japanese Kokai No. 60-23,312,corticosteroids are used to prevent inflammation due to retainedmoisture. As to alleviation of the elicited allergic reaction as notedabove, corticosteroids work to slightly reduce inflammation but do notexhibit their full anti-inflammatory effects until most of thesensitizing drug has been removed from the sensitized area.

Accordingly, prior to our invention, the topical application ofcorticosteroids either alone or in combination with other drugs, was notknown to provide any beneficial effect during the induction phase ofsensitization and was even contraindicated because it tended to mask theelicitation phase. See Drug Information 86, 84:06, "Anti-InflammatoryAgents: Topical Corticosteroids General Statement", at page 1781,pp1780-82, American Hospital Formulary Service (1986).

For the above stated reasons, our discovery that corticosteroidscoadministered with sensitizing drugs according to our invention,actually prevents the induction of sensitization, is truly unobvious.

According to our invention, we have found that co-extensivecoadministration of a corticosteroid with a drug which tends tosensitize the skin upon prolonged exposure, can prevent the inductionphase of sensitization or reduce it significantly. This isdistinguishable from agents which act to reduce irritation.

SUMMARY OF THE INVENTION

An object of the present invention is to prevent contact sensitizationinherent in the transdermal administration of numerous drugs.

A further object of the present invention is to eliminate the inductionphase of sensitization.

These and other objects have been demonstrated by the present inventionwherein a sensitizing drug and a corticosteroid are transdermallycoadministered as a composition of matter which may take the form of amatrix in a transdermal therapeutic system or of a formulation appliedto the skin as an ointment, gel or cream.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a cross-sectional view of one embodiment of a transdermaltherapeutic system according to this invention.

FIG. 2 is a cross-sectional view of another embodiment of a transdermaltherapeutic system according to this invention.

DESCRIPTION OF THE PREFERRED EMBODIMENT

According to our invention, we have discovered that continuallycoadministering a corticosteroid with drugs and other beneficial agents,will prevent the occurrence of the induction phase of sensitization. Inorder to produce the effects obtained herein which are not obtainedaccording to the prior art: (1) the corticosteroid must be delivered attherapeutically effective rates, i.e. sensitization induction preventingrates, or in therapeutically effective amounts and; (2) thecorticosteroid must be delivered at such rates throughout the periodduring which the drug is present in the skin. These two featuresdistinguish our invention from the prior art in which insufficientcorticosteroid was present, the corticosteroid was not present in a formtransdermally administrable at the required rates or both.

In one embodiment of our invention, both the drug and the corticosteroidare simultaneously delivered for the entire delivery period, i.e.co-extensive coadministration. In another embodiment of this invention,co-extensive coadministration is preceded by delivery of thecorticosteroid alone, for a specified period of time. In still anotherembodiment of the invention, the corticosteroid is delivered for aportion of the time in which the drug is delivered.

As used herein the term "drug" relates to a biologically active agent,compound or composition of matter which is administered for the purposeof providing some beneficial or therapeutic effect. As used herein, theterm "transdermal" delivery relates to the delivery of a drug by passagethrough skin or mucosa by topical application.

According to our invention, a corticosteroid and the sensitizing drug tobe delivered are placed in drug and corticosteroid transmittingrelationship to the appropriate body surface, preferably in a carriertherefore, and maintained in place for the desired period of time. Thedrug and corticosteroid are typically dispersed within a physiologicallycompatible matrix or carrier which may be applied directly to the bodyas an ointment, gel, cream, suppository or sublingual or buccal tablet,for example, but are more preferably administered from a transdermaltherapeutic system as more fully described below.

This invention has proven utility in connection with the delivery ofchlorpheniramine maleate. It is anticipated that coadministration of acorticosteroid according to our invention with known sensitizing drugssuch as clonidine, tetracaine, naloxone, naltrexone and nalbuphine alongwith narcotic analgesics such as buprenorphine, hydromorphone andlevorphanol, will prevent sensitization. It is also anticipated thatthis invention has utility in connection with the delivery of drugswithin the broad class normally delivered through body surfaces andmembranes, including skin. In general, this includes therapeutic agentsin all of the major therapeutic areas including, but not limited to,anti-infectives, such as antibiotics and antiviral agents, analgesicsand analgesic combinations, anorexics, antiarthritics, antiasthmaticagents, anticonvulsants, antidepressants, antidiabetic agents,antidiarrheals, antihistamines, anti-inflammatory agents, antimigrainepreparations, antimotion sickness preparations, antinauseants,antineoplastics, antiparkinsonism drugs, antipruritics, antipsychotics,antipyretics, antispasmodics, including gastrointestinal and urinary;anticholinergics, sympathomimetics, xanthine derivatives, cardiovascularpreparations including calcium channel blockers, beta-blockers,antiarrythmics, antihypertensives, diuretics, vasodilators, includinggeneral, coronary, peripheral and cerebral, central nervous systemstimulants, cough and cold preparations, decongestants, diagnostics,hormones, hypnotics, immunosuppressives, muscle relaxants,parasympatholytics, parasympathomimetics, psychostimulants, sedativesand tranquilizers.

The invention is best understood when viewed in light of the followingrelationships. For a given drug delivery system, certain parameters arepredetermined. One such parameter is the therapeutically effective drugdelivery rate, J_(d) (μg/cm² -hr). Given a set delivery time period t(hrs) the amount of drug which will be delivered per unit area x_(d)(μg/cm²) can be determined. In such systems, a sufficient amount of drugexists in the reservoir to maintain the necessary concentration gradientwhich acts as the driving force to maintain said rate for thepredetermined time, t (hrs). Normally, an excess of drug over saturationis used when a constant steady drug delivery rate is desired. Typically,this excess is calculated by determining the amount of drug needed tohave a saturated system and adding to this value, the amount of drugwhich is going to be delivered (x_(d)) and an excess to act as a "safetyfactor" to provide continuous delivery at the required rates. Thedelivered amount is shown by the equation x_(d) /J_(d) =t or x_(d)=(J_(d))(t).

In this invention, the corticosteroid preferably is continuouslyco-administered, ie. as long as the sensitizing drug is either beingdelivered or is present in the skin, the corticosteroid is also beingdelivered. An important parameter is the induction preventing rate J_(c)(μg/cm² -hr) which is essentially the corticosteroid delivery rate. TheJ_(c) value is the net delivery rate, taking into account the use of anypermeation enhancers which help to achieve that rate. Since the time thas already been determined by the therapeutic requirements of thesystem, the basic equation is x_(d) /J_(d) =t=x_(c) /J_(c), where x_(c)is the amount of corticosteroid per unit area which will be delivered tothe skin. Just as with the drug, the corticosteroid must be present inexcess, to provide that the corticosteroid is continuously deliveredwith the drug and continues to be present as long as any drug is presentin the epidermis. Therefore, for a system where J_(d), x_(d), t andJ_(c) are known, the amount of corticosteroid to be placed in the systemcan be determined by calculating the amount needed to saturate thesystem plus the amount which is to be delivered (x_(c) =(J_(c))(t)),plus an excess amount as a "safety factor".

Especially good results have been achieved using hydrocortisone as thecorticosteroid. Hydrocortisone esters such as hydrocortisone acetate,are also suitable. More potent corticosteroids may not require apermeation enhancer as hydrocortisone and hydrocortisone acetate do.However, the advantages of hydrocortisone or its esters such ashydrocortisone acetate, is that they do not damage the skin uponprolonged exposure and they are approved for over-the-counter use. Thisinvention contemplates the use of any corticosteroid in addition tohydrocortisone and includes, without limitation, beclomethasone,betamethasone, benzoid, betamethasone dipropionate, betamethasonevalerate, clobetasol propionate, clobetasol butyrate, desonide,dexamethasone, fluocinonide, prednisolone and triamcinolone, forexample.

The necessary concentration of corticosteriod in the epidermis can beachieved by the addition of flux enhancers and controlled release of thesteroid. The desired flux rate of the corticosteroid will vary fromcorticosteroid to corticosteroid, but is typically about 0.01 to 5μg/cm² -hr. For certain corticosteroids, this flux rate can be obtainedwithout the addition of permeation enhancers. However, withcorticosteroids such as hydrocortisone and hydrocortisone esters, apermeation enhancer is usually necessary to achieve the desired fluxrate. Suitable permeation enhancers for corticosteroids are known to theart and include, without limitation, oily surfactants such as sucrosemonolaurate and glycerol monooleate, alcohols and keratinolgtic agents.

One embodiment of this invention is the transdermal delivery of asensitizing drug and a corticosteroid by application of a formulation tothe skin surface, which may be aqueous or non-aqueous based. Theseformulations can be designed to deliver the sensitizing drug and thecorticosteroid at the desired fluxes and can be in numerous forms,including without limitation, ointments, gels and creams.

Aqueous formulations, specifically gels, typically comprise water andabout 1-2 weight % of a gelling agent such as hydroxyethyl cellulose orhydroxypropyl cellulose. Typical non-aqueous gels are comprised ofsilicone fluid or mineral oil, the latter of which may also have 1-2weight % of a gelling agent such as colloidal silicon dioxide. Thesuitability of a particular gel depends upon the compatibility of itsconstituents with both the sensitizing drug and corticosteroid, alongwith the permeation enhancer, if any.

EXAMPLE I

Testing protection from sensitization by use of hydrocortisone, was doneon two groups (40 subjects each) of adult females. Group I received gelscontaining, by weight percent: 8% dex-chlorpheniramine maleate (DCPM),2% hydrocortisone, 5% sucrose monolaurate, 4% hydroxyethyl cellulose and81% water. Group II received gels containing, by weight percent: 8%DCPM, 4% hydroxyethyl cellulose and 88% water.

These gel applications contained up to 25 mg DCPM and provided a DCPMtransdermal permeation rate of about 10-15 μg/cm² -hr. The drugconcentration was such that, as calculated from results of skinpermeation studies using human skin in vitro, the transdermal permeationrate of DCPM was no greater than 0.72 mg/day. For the gels containinghydrocortisone, the flux rate of corticosteroid was about 0.5-1.0 μg/cm²-hr or up to 0.05 mg/day for a 2 cm² system.

Gels were placed in standard 2 cm² patch test devices, and applied forthree weeks to the same spot, exchanging about every other day. Twoweeks after removal of the ninth gel, subjects received an applicationof the gel to which they had been previously exposed, to a new skinarea. Forty-eight hours later, the gel was removed and another, similarone, applied to the same area. After an additional 48 hours ofresidence, the second gel was removed.

Reactions were observed 48 and 96 hours after the last removal. Theresults were as follows: in Group II, 16 subjects experiencedsensitization, while in Group I which used the gel containinghydrocortisone, only 2 subjects experienced any sensitization. In thismanner, coadministration of hydrocortisone prevents topicalsensitization to DCPM prophylactically.

EXAMPLE II

A challenge was done to the experiment described in Example I. As statedabove, of the 40 subjects in Group I (drug plus hydrocortisone) 2experienced sensitization, leaving 38 who were not sensitized. Of the 40subjects in Group II (drug alone) 16 subjects experienced sensitization,leaving 24 who were not sensitized.

Approximately one month after the completion of the experiment inExample I, the subjects who had not become sensitized were once againsubjected to the same test conditions as before, except that both groupsreceived both test items, i.e. DCPM gels alone and DCPM gels containinghydrocortisone. Of the 38 subjects in Group I, 1 subject responded andof the 24 subjects in Group II, 2 responded. All three of these subjectsresponded to both test items, indicating that once sensitized, thepresence of hydrocortisone does not prevent a skin reaction in theallergic individual.

Combining the long term evaluation results of the original and thechallenging experiment reveals that of 40 subjects receiving a gelcontaining dex-chlorpheniramine and hydrocortisone, only 3 experiencedany sensitization. Of the 40 receiving a gel containingdex-chlorpheniramine along, 18 became sensitized. The challenge to theresults of Example I was done to prove that hydrocortisone specifically,and corticosteroids generally, suppress the induction phase ofsensitization, not the elicitation phase.

Referring now to FIG. 1, a transdermal therapeutic system 10 accordingto this invention is shown. The system 10 comprises a sensitizing drugreservoir 12 covered by an impermeable backing 14, and a ratecontrolling membrane 16. The system 10 adheres to the surface of theskin 20 by means of an in-line contact adhesive 18. This adhesive layer18 contains a set amount of corticosteroid. A strippable release liner,not shown, adapted to be removed prior to application would normally beincluded in the packaged product.

In an alternate embodiment, the system is attached by means of anadhesive overlay, as is shown in FIG. 2. The system 22 is comprised of asensitizing drug/ corticosteroid reservoir 24 which is in the form of amatrix or carrier having the drug and the corticosteroid dispersedthroughout. The reservoir 24 is covered by an impermeable backing 26which is preferably sized larger in circumference than the reservoir 24.Means 28 for maintaining the system on the skin may be fabricatedtogether with or provided separately from the remaining elements of thesystem. Means 28 as illustrated in FIG. 2 takes the form of an adhesiveoverlay. In some instances, an adhesive overlay 28 is preferable over anin-line contact adhesive 18 as shown in FIG. 1. This is true when thereare elements present in the matrix which may adversely affect theadhesive properties of most pharmaceutically acceptable contactadhesives. For this reason, impermeable backing layer 26 is preferablysized slightly larger than the reservoir 24 to provide a peripheral areaaround the reservoir 24, which would be free of any material which mayseep from under the base of reservoir 24 and adversely interact with theadhesive in overlay 28. A strippable release liner 30 would also beprovided with the system 22, to be removed prior to use.

Various materials suited for the fabrication of the various layers aredisclosed in the aforementioned patents. The composition of the matrixmay, depending on the drug to be delivered, be either an aqueous oranhydrous base. Suitable matrices or carriers are described in the aboveidentified patents and include, without limitation, natural andsynthetic rubbers such as polybutylene, polyisobutylene, polybutadiene,polyethylene, styrenebutadiene copolymers, polyisoprene, polyurethane,ethylene/propylene copolymers, polyalkylacrylate polymers, copolyesters,ethylene/acrylic copolymers, silicones and butadiene/acrylonitrilecopolymers for example and other polymers such as the ethylenevinylacetate (EVA) polymers described in U.S. Pat. No. 4,144,317 (whichis incorporated herein by reference). Other suitable materials includegelled or thickened mineral oil, petroleum jelly and various aqueousgels and hydrophilic polymers. Typically the drug is dispersed throughthe matrix or carrier at a concentration in excess of saturation, theamount of excess being a function of the intended useful life of thesystem. The drug may, however, be present at initial levels belowsaturation without departing from this invention.

In addition to the sensitizing drug and the corticosteroid, which areessential to the invention, the matrix may also contain other materialssuch as dyes, pigments, inert fillers, permeation enhancers, excipientsand other conventional components of pharmaceutical products ortransdermal therapeutic systems known to the art.

This invention does not require any pretreatment of the skin site withthe corticosteroid. Inclusion of the corticosteroid can be in the drugreservoir and/or other drug releasing compartment of a transdermaltherapeutic system. In some instances, there is great disparity betweenthe drug flux and the corticosteroid flux. In such cases, thecorticosteroid is preferably placed in the adhesive, as in FIG. 2. Onthe other hand, where there is no great disparity in fluxes, both thedrug and the corticosteroid may be placed together in the reservoir, asin FIG. 1.

The applications and usefulness of this invention as it applies totransdermal systems is best understood in light of the followingexamples.

EXAMPLE III

Clonidine transdermal drug delivery systems have been found to elicitcontact dermatitis in a significant number of patients, to whom thesystems are repeatedly applied.

A transdermal therapeutic system as described with respect to FIG. 1 forthe delivery of clonidine would be suitable for use in eliminatingsensitization caused by clonidine. The system 10 would be fabricatedusing hydrocortisone as the corticosteroid. Hydrocortisone would bepresent both in the reservoir 12 and in the adhesive 18. Thehydrocortisone would be present in the adhesive layer 18 in an amount inexcess of saturation as the adhesive acts as the hydrocortisonereservoir. However, hydrocortisone may also be present to some degree inthe drug reservoir 12. Coadministration of hydrocortisone with clonidineis expected to counter any topical sensitization to the drug.

Typical clonidine delivery systems are described in Enscore, et al, U.S.Pat. No. 4,559,222 incorporated herein by reference. A typical releaserate in vitro at 32° C. for clonidine is 1.6 μg/cm² -hr. For a 7 day(168 hour) delivery system, assuming hydrocortisone is being deliveredat a rate in the range of 0.5-1.0 μg/cm² -hr, at least 84-168 μg/cm² ofhydrocortisone will be delivered during the 7 days. To maintain thenecessary concentration gradient driving force, hydrocortisone must bepresent in the adhesive in a concentration in excess of saturation. Theexcess must be at least 84-168 μg/cm², the amount of hydrocortisone tobe delivered in a 7 day period, in order to attain continuousadministration of hydrocortisone and thereby prevent the induction ofsensitization.

EXAMPLE IV

U.S. Pat. No. 4,559,222 also describes a scopolamine drug deliverysystem. Just as with the clonidine system of Example III, a 7 day systemfor example, would require a saturation concentration plus at least84-168 μg/cm² of hydrocortisone in the adhesive layer of the system.

EXAMPLE V

Tetracaine is also known to elicit sensitization. A transdermaltherapeutic system as described with respect to FIG. 2 for the deliveryof tetracaine would be suitable for use in eliminating the sensitizationcaused by tetracaine. The system 22 would comprise a reservoir 24containing the tetracaine and an appropriate corticosteroid, such ashydrocortisone. Coadministration of the corticosteroid with tetracaineis expected to counter any sensitization to the drug.

As stated above in Examples III and IV, for a 7 day delivery system,given a hydrocortisone delivery rate in the range of 0.5-1.0 μg/cm² -hr,at least 84-168 μg/cm² of hydrocortisone will be delivered during the 7days. To maintain the necessary driving force, saturation concentrationplus at least 84-168 μg/cm² of hydrocortisone would be required toprevent the induction phase of sensitization.

EXAMPLE VI

Transdermal drug systems for the delivery of naloxone, naltrexone andnalbuphine have also been found to elicit sensitization in some patientsto whom the systems are repeatedly applied. Typical systems aredisclosed in Cheng, et al, U.S. Pat. No. 4,573,995, incorporated hereinby reference.

A transdermal therapeutic system as described with respect to FIG. 2 forthe delivery of these drugs in their base form would be suitable for usein eliminating the sensitization caused by the drug. The system 22 wouldcomprise a reservoir 24 containing the base form of naloxone, naltrexoneor nalbuphine and an appropriate corticosteroid, such as beclomethasone.Coadministration of the corticosteroid with the drug is expected tocounter any sensitization to the drug.

As stated earlier, suitable corticosteroid flux rates are about 0.01-5.0μg/cm² -hr. For a 7 day delivery system using beclomethasone, at least1.68-840 μg/cm² of beclomethasone will delivered during the 7 days. Tomaintain the driving force then, beclomethasone must be present in thesystem in excess of its saturation concentration, said excess being atleast 1.68-840 μg/cm².

Additionally, since the chemical make-up of some narcotic analgesicssuch as levorphanol, hydromorphone and buprenorphine is similar to thatof naloxone, naltrexone and nalbuphine, it is expected that thesensitization which they induce, will likewise be prevented by theinclusion of a corticosteroid as described by this invention.

The transdermal coadministration of clonidine, scopolamine, tetracaine,naloxone, naltrexone, nalbuphine, levorphanol, hydromorphone andbuprenorphine with a corticosteroid, according to our invention, canalso be achieved by means of a gel as in Example I. The sensitizingdrug, corticosteroid and permeation enhancer (if necessary) can beincorporated in a typical aqueous or non-aqueous gel. The amount of drugincorporated into the gel composition is determined by the therapeuticdelivery rate needed for effective treatment. The amount ofcorticosteroid, on the other hand, is determined by the duration of drugdelivery in that the corticosteroid is present in the gel in an amountsufficient for continuous coadministration with the drug.

This invention has been described in detail with further reference tocertain preferred embodiments thereof, but it will be understood thatvariations and modifications can be effected within the spirit and scopeof the invention.

What is claimed is:
 1. A medical device for transdermal administrationof a skin sensitizing drug to a human in need thereof without inducingskin sensitization in the human, comprising in combination:a) areservoir means containing said sensitizing drug and a corticosteroid;b) a means for maintaining said reservoir means in drug-transmitting andcorticosteroid-transmitting relationship to a selected skin site; c)said drug being present in said reservoir means in an amount sufficientto deliver said drug to the selected skin site at a therapeuticallyeffective rate for a predetermined time period; and d) saidcorticosteroid being present in said reservoir means in an amount inexcess of that required to deliver said corticosteroid to the selectedskin site at a sensitization induction preventing rate for saidpredetermined time period.
 2. The device of claim 1 wherein said meansfor maintaining said reservoir in drug and corticosteroid transmittingrelationship to the selected skin site comprises an in-line contactadhesive.
 3. The device of claim 1 wherein said means for maintainingsaid reservoir in drug and corticosteroid transmitting relationship tothe selected skin site comprises an adhesive overlay.
 4. The device ofclaim 1, wherein said corticosteroid comprises hydrocotisone.
 5. Thedevice of claim 1, further comprising a rate controlling membrane. 6.The device of claim 4, wherein said hydrocortisone is present in saidreservoir means in an amount in excess of that required to deliver saidhydrocortisone at a sensitization induction preventing flux within therange of about 0.01-5 μg/cm² -hr.
 7. The device of claim 4, wherein saidhydrocortisone is present in said reservoir means in an amount in excessof that required to deliver said hydrocortisone at a sensitizationinduction preventing flux within the range of about 0.5-1.0 μg/cm² -hr.8. The device of claim 1, wherein said sensitization inductionpreventing rate is achieved by a corticosteroid permeation enhancer inthe reservoir means.
 9. The device of claim 1, wherein said drug isselected from the group consisting of clonidine, scopolamine,tetracaine, chlorpheniramine maleate, naloxone, naltrexone, nalbuphine,levorphanol, hydromorphone and buprenorphine.
 10. The device of claim 1,wherein said drug comprises clonidine.
 11. The device of claim 10,wherein said corticosteroid is selected form the group consisting ofhydrocortisone, hydrocortisone acetate, hydrocortisone esters,beclomethasone, betamethasone, benzoid, betamethasone dipropionate,betamethasone valerate, clobetasol propionate, clobetasol butyrate,desonide, dexamethasone, fluocinonide, prednisolone and triamcinolone.12. The device of claim 1, wherein said predetermined time period isabout 7 days.
 13. The device of claim 1, wherein said drug compriseschlorpheniramine.
 14. The device of claim 13, wherein saidchlorpheniramine is in a form selected from the group consisting ofchlorpheniramine maleate and dex-chlorpheniramine maleate.
 15. Thedevice of claim 13, wherein said corticosteroid compriseshydrocortisone.